By the classical research of Bloch, Cornforth, Lynen and coworkers, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) have become established as key intermediates in the biosynthesis of isoprenoids via mevalonic acid.
Bacteria, plants and the protist Plasmodium falciparum synthesize isoprenoids by an alternative pathway via 1-deoxy-D-xylulose 5-phosphate. This non-mevalonate pathway has so far only been partially explored (FIG. 1), but its absence in animals makes it an ideal target for pesticidal or medical purposes. Moreover, the idiosyncratic nature of the reactions in this pathway reduces the risk of cross-inhibitions with other, notably mammalian enzymes. For a better understanding of these aspects of the invention, the pathway shall be briefly explained. It begins with a condensation of pyruvate (1) with glycerolaldehyde 3-phosphate (2) to 1-deoxy-D-xylulose 5-phosphate (DXP) (3). Subsequently, DXP is converted to 2C-methyl-D-erythritol 4-phosphate (4) by a two-step reaction comprising a rearrangement and a reduction. The subsequent steps to isoprenoids have so far not been explored, but it may be assumed that the pathway includes intermediates of the type IPP and DMAPP. In any event, this pathway and notably these subsequent enzymatic steps are here determined to be ideal targets in screening chemical libraries for inhibitors.
The non-mevalonate pathway (alternative isoprenoid pathway), with which the present invention is concerned, generates the basic isoprenoid C5-compounds (IPP and/or DMAPP or an equivalent compound) from which all higher isoprenoids derive by downstream biosynthetic pathways. Higher isoprenoids are called terpenoids. Therefore, any inhibitor of an enzyme in the non-mevalonate pathway is at the same time an inhibitor of all subsequent isoprenoid pathways, i.e. an inhibitor of the terpenoid pathways.
Wherever a phosphorylated compound or a carboxylic acid compound is mentioned it may exist as a free acid or as a salt with at least one proton replaced by ammonium or a metal ion or an organic cation. The metal ion may be an alkali metal ion or an alkaline earth metal ion. The organic cation may be derived from an amine. It may be a sulfonium ion, a guanidinium ion or a heteroaromatic ion. Such a phosphorylated compound, when in an aqueous solution, will exist in an equilibrium dissociation state.